Method of protection against growth of microorganisms with organo-bismuth compound



United States Patent METHOD OF PROTECTION AGAINST GROWTH OF MICROORGANISMS WITH ORGANO-BIS- MUTH COMPOUND John R. Leebrick, Roselle Park, N.J., assignor to Metal & Thermit Corporation, Woodbridge Township, N..l., a corporation of New Jersey No Drawing. Filed Dec. 13, 1962, Ser. No. 244,252

23 Claims. (Cl. 167-42) This invention relates to methods of preventing and inhibiting the growth of microorganisms including bacteria and to compositions of matter utilized in these methods. The invention also relates to materials which have been made resistant to attack by microorganisms such as bacteria.

It is an object of this invention to provide methods for inhibiting and preventing the growth of microorganisms. It is still another object of the invention to provide bacteria-resistant compositions including paints, plastics, and fibrous products such as textiles and paper products. It is also an object of this invention to provide sanitizer compositions having particular utility in hospital treatment. Other objects will be apparent to those skilled in the art on inspection of the following description.

In accordance with certain of its aspects, the method of this invention for protecting a medium susceptible to attack by microorganisms comprises applying to the locus to be protected, an effective amount of R Bi wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl.

In the compounds R Bi, which may be used in practice of this invention, R may be alkyl, cycloalkyl, alkenyl, cycloalkenyl, or alkynyl, including such groups when inertly substituted. When R is alkyl, it may include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-amyl, n-octyl, Z-ethylhexyl, etc. as well as substituted alkyls including phenyl ethyl, b-enzyl, etc. Typical alkenyl groups which may be employed may include vinyl, 2- propenyl (i.e., allyl), l-propenyl, l-butenyl, Z-butenyl, etc. as well as inertly substituted alkcnyl groups typified by 4-phcnyl, buten-l-yl, etc. Typically cycloalkyl groups may include cyclohcxyl, cycloheptyl, cyclooctyl as well as incrtly substituted eycloalkyl groups including 2-methyl cycloheptyl, 3-butyl cyclohexyl, 3-methyl cyclohexyl, etc. Typical aikynyl groups which may be employed include propyn-l-yl, propyn-Z-yl, butyn-l-yl, phenlethyn-yl, ethynyl.etc.

Preferably R may be an alkyl group having from three to eight carbon atoms, e.g., n-propyl, i-propyl, n-butyl, i-butyl, n-amyl, n-hexyl, 2-ethylhexyl, cyclohexyl, and octyl. The preferred R may be butyl,

Typical specific compounds which maybe employed in practice of this invention may include trimethyl bismuth, triethyl bismuth tri-n-propyl bismuth, tri-i-propyl bismuth, tri-n-butyl bismuth, tri-i-butyl bismuth, tri-n-amyl bismuth, tri-i-amyl bismuth, tri-n-hexyl bismuth, tri-cyclohexyl bismuth, tri-n-heptyl bismuth, tri-eycloheptyl bismuth, tri-moctyl bismuth, tri-Z-ethylhexyl bismuth, tri-ndecyl bismuth, tri-tetradecyl bismuth, tri-vinyl bismuth, tri-allyl bismuth, tri-cyclohexenyl bismuth, tripropynyl bismuth, and triphenylcthynyl bismuth.

Preferred compounds may include those wherein R may have from about three to about eight carbon atoms. Typical specific preferred compounds include trin-butyl bismuth, tri-n-octyl bismuth, tri-n-propyl bismuth, tricyclohexyl bismuth, and tri-n-hexyl bismuth.

These compounds may be available or may be readily made in the laboratory. For example, they may be made by the reaction of bismuth trichloride with, e.g., the appropriate Grignard reagent.

3,247,051 Patented Apr. 19, 1966 it is a particular feature of this invention that bismuth compounds R Bi may be used to control a wide range of microorganisms including bacteria. The compounds of this invention are highly effective against a wide spectrum of bacteria including Gram negative and Gram positive bacteria. Typical Gram positive bacteria against which the technique of this invention may be particularly effective may include S. aureus. Typical Gram negative bacteria which may be controlled in accordance with certain aspects of this invention may include A. aerogenes and P. aeruginosa. It is a particular feature of this invention that in accordance with certain aspects it may be used to control fungi including C. nlbicans, A. flaws, and

P. fmziculosum.

In practice of this invention, these microorganisms and preferably bacteria may be controlled in a wide variety of loci. It is possible according to this invention to treat plastics, textiles, paper products, paints, and other specific materials which may serve as media in which microorganisms may grow. Plastics, textiles, paper products, and paints may be illustrative of the materials which are rendered resistant to attack when treated by applying the bismuth compound to the surface and/or by incorporation therein. The plastics in massive and in fiber form may include urethanes, halogenated polymers and copolymers such as polyvinyl chloride and polyvinyl chloride-polyvinyl acetate copolymers, polyesters, polyamides, polyolefins, and natural or synthetic rubbers, etc. Natural fiber products that may be protected may include paper products, hemp, and felts. Paints may be protected during storage and after application. Typical paints may include interior and exterior vinyl latex and alkyd paints, non-synthetic fiat natural paints, acrylic paints, and anti-fouling paints containing acrylic and vinyl components. The process of this invention may be used in preserving adhesives; in secondary oil recovery processes; in paper mill slime control processes; and in controlling S. aureus in hospitals. The novel compositions of this invention may be active components of detergent sanitizers and may be used for this and other purposes in the form of an aerosol material. They may also be used to protect plants and other growths against attack by microorganisms.

Practice of this invention may be illustrated by reference to the following wherein various compounds were used to treat a wide range of microorganisms. In Table I, there is disclosed the results of the standard Broth Dilution Test wherein various compounds as noted were tested against bacteria.

In the tables showing the Broth Dilution Test results, the tests are reported showing the activity of the compounds against noted microorganisms. In each example. a series of tests was carried out in which the compound was placed within a nutrient broth in amount of 500, 250, 125, 63, 31, 16, 8, 4, and 2 parts per million (p.p.m.). Each broth was inoculated with the test organism and the broth incubated at 37 C. for two days. The organism growth was visually observed. The broth containing the minimum concentration which caused complete inhibition of the growth of the organism is listed.

TABLE I. *TI I Il BUTYL BISMUTII Microorganism: Conc., p.p.m. S. awreus 0.5 A. aerogenes 4 P. aeruginosa 2 From Table I, is will be apparent that the noted compounds may be employed in unexpectedly low levels to kill both Gram negative and Gram positive bacteria. As

will be apparent to those skilled in the ant, these compounds are unexpectedly highly effective.

In Table II, there are listed the results of a standard Broth Dilution Test against certain fungi.

TABLE IL-TltI-n-BUTYL BISMUTH Microorganism: Cone, p.p.m. C. albicans 63 A. flavus 250 P. funiculosum 250 From Table II, it will be apparent to those skilled in the art that the compounds of this invention unexpectedly exhibit activity against fungi.

It is a particular feature of this invention that the preferred formulations prepared in accordance therewith possess an unexpectedly high activity against Gram negative bacteria. It will be obvious to those skilled in the art that prior art bactericides possess little or no activity against Gram negative bacteria when used in concentrations at which the preferred formulations of this invention (i.e., those containing tri-n-butyl bismuth) may control a wide range of biocidal targets including Gram negative bacteria. For example in a comparison by means of a Broth Dilution Test against phenyl mercury acetate (a typical active prior art bactericide), it was found that tri-n-butyl bismuth was about four times as effective as phenyl mercury acetate as noted in the table.

TABLE 111 Compound: P. acruginosa Tri-n-butyl bismuth 2 Phenyl mercury acetate 8 The method of this invention may be effected by using the noted compound R 81 in solid, liquid, or gaseous (including spray) formulations which preferably may include a carrier or diluent. It may, for example, be carried out by applying the compound to the surface of the material to be protected and/or admixing the compound with the material to be protected during the fabrication of said material. The compounds may be used per se, particularly when they are incorporated into the material during preparation or fabrication. Many materials, particularly fibrous products such as textiles, may be treated by applying the compound to the surface by dipping, padding, spraying, etc. They may be used in the form of a bactericidal composition in which the compound is the active component or one of the active components. Liquid compositions may be utilized in which the compound is dissolved and/or suspended in a solvent. Solid compositions may be utilized in which the compound is mixed with a carrier or diluent. The carrier may be inert, such as talc, clay, diatomaceous earth, flour, etc., or it may have activity such as that shown by the quaternary ammonium compounds. The liquid formulations of the emulsion type may often include a dispersing agent such as an anionic, cationic, or nonionic surface active agent. To obtain a bactericidal composition having an extremely broad spectrum of activity, the compounds may be formulated with other active materials such as the triorganotins, pentachlorophenyl, copper-8-quinolinolate, bisphenols, o-phenylphenol, and polybrominated salicylanilides.

It will be apparent to those skilled in the art that the amount of the active compound R Bi present in the total composition may be sufiicent to provide and effective amount at the locus to be protected against the appropriate microorganism. Typically such contained amounts may range from very low concentrations typically 0.001% or 0.002% up to 90%-l00%. When the carrier is a solid, e.g., talc, the compound may be present in amount of %-50%, say 20% of the total; when the carrier is a liquid, e.g., isopropanol-Frcon (under pressure), the compound may be present in an amount of 0.0l%1%, say 0.05%. These concentrations may permit attainment on or in the medium susceptible to attack at the locus to be protected, of effective amounts. Such amounts may be, e.g., in water treatment, 1-100 ppm. or in plastic treatment, 10-2000 p.p.m., etc. Illustrative of the compositions containing the active bismuth compound may be those of Examples 1-4.

Example 1.Aeros0l composition Parts by weight It is a particular feature of the process of this invention that it permits attainment of a high degree of control of, e.g., E. coli and S. aureus when used in a polyvinyl acetate outside paint. In this test, a standard paint, Sunoco PVA paint, was mixed with the amount of trin-bu'tyl bismuth noted in column 1 of Table IV and applied to 10 mm. filter paper discs. AATCC Bacteriostasis agar, held at 45 C., was inoculated to 1% with an 18-24 hour nutrient broth culture of S. aurcus or E. coli. The seeded agar was distributed at the rate of 15 ml./ 10 cm. petri dish and allowed to solidify. The treated filter paper discs were placed on the seeded agar. Then the plates were incubated at 37 C. for 78 hours. Inhibition was determined by a zone or halo aujacent to the treated disc.

TABLE IV Concentration, percent S. Anrcus, 1;. Colt,

It will be apparent from inspection of the above table that use of a paint which may be prepared in accordance with this invention permits attainment of high resistance to Gram negative and Gram positive bacteria.

Specific formulations which may be used in practice of this invention may include those set forth in Examples 5-7.

Example 5.-Acryt'ic anti-fouling pain! Parts by weight Tri-cyclohexyl bismuth M Example 7.F lat interior paint Titanium-calcium pigment 25 Calcium carbonate 100 Magnesium silicate 25 Ester gum solution (60% non-volatile in mineral spirits) 30 Bodied linseed oil 200 Mineral spirits 167 Cobalt naphthenate (6% Co) 1 Lead naphthenate (24% Pb) 2 Tri-n-propyl bismuth 6 Those skilled in the art will appreciate that other organobismuth compounds as defined herein can be employed in the compositions and methods of the invention to protect a wide variety of materials and living organisms that are susceptible to attack by microorganisms. As many embodiments of this invention may be made without departing from the spirit and scope thereof, it is to be understood that the invention includes all such modifications as come within the scope of the appended claims.

I claim:

1. The method for protecting plastics, textiles, natural fibers materials, adhesives, oil wells, paper mills, and has pitals from attack by Gram negative bacteria, Gram positive bacteria and fungi which comprises applying to the locus to be protected an eiicctive amount of a compound RgBi wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and cyloalkenyl.

2. The method for protecting plastics, textiles, natural fiber materials, adhesives, oil wells, paper mills, and hospitals from attack by Gram negative bacteria, Gram positive bacteria and fungi as claimed in claim 1 wherein R is an alkyl group containing 3-8 carbon atoms.

3. The method for protecting plastics, textiles, natural fiber materials, adhesives, oil wells, paper mills, and hospitals from attack by Gram negative bacteria, Gram positive bacteria and fungi as claimed in claim 1 wherein said compound is tri-n-butyl bismuth.

4. The method for protecting plastics, textiles, natural fiber materials, adhesives, oil wells, paper mills, and hospitals from attack by Gram negative bacteria, Gram positive bacteria and fungi as claimed in claim 1 wherein said compound is tri-n-octyl bismuth.

5. The method for protecting plastics, textiles, natural fiber materials, adhesives, oil wells, paper mills, and hospitals from attack by Gram negative bacteria, Gram positive bacteria and fungi as claimed in claim 1 wherein said compound is tri-n-propyl bismuth.

6. The method for protecting plastics, textiles, natural fiber materials, adhesives, oil wells, paper mills, and hospitals from attack by Gram negative bacteria, Gram positive bacteria and fungi as claimed in claim 1 wherein said compound is tri-cyclohexyl bismuth.

7. The method for protecting plastics, textiles, natural fiber materials, adhesives, oil wells, paper mills, and hospitals from attack by Gram negative bacteria, Gram positive bacteria and fungi as claimed in claim 1 wherein said compound is tri-n-hexyl bismuth.

8. A composition active against microorganisms comprising an inert carrier; and as the active component 0.01 to 50% by weight of the composition of a bismuth compound R Bi wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl; and a dispersing agent.

9. A composition active against microorganisms as claimed in claim 8 wherein R is an alkyl group containing 3-8 carbon atoms.

10. A composition active against microorganisms as claimed in claim 8 wherein said compound is tri-n-butyl bismuth.

11. A composition active against microorganisms as claimed in claim 8 wherein said compound is tri-n-octyl bismuth.

12. A composition active against microorganisms as claimed in claim 8 wherein said compound is tri-n-propyl bismuth.

13. A composition active against microorganisms as claimed in claim 8 wherein said compound is tricyclohexyl bismuth.

14. A composition active against microorganisms as claimed in claim 8 wherein said compound is tri-n-hexyl bismuth.

15. A composition active against microorganisms comprising a solid carrier and as the active component a fungicidal amount of a bismuth compound RgBl wherein R is selected from the group consisting of alkyl, alkenyl alkynyl, cycloalkyl, and cycloalkenyl.

16. A composition active against microorganisms comprising a solid carrier and as the active component, a bismuth compound R Bi wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl, said bismuth compound being present in the amount of 5-50% by weight of the total composition.

17. A composition active against microorganisms as claimed in claim 16 wherein R is an alkyl group containing 3-8 carbon atoms.

18. A composition active against microorganisms as claimed in claim 16 wherein said compound is tri-n-butyl bismuth.

19. A composition active against microorganisms as claimed in claim 16 wherein said compound is tri-n-octyl bismuth.

20. A composition active against microorganisms as claimed in claim 16 wherein said compound is trinpropyl bismuth.

21. A composition active against microorganisms as claimed in claim 16 wherein said compound is tri-cyclohexyl bismuth.

22. A composition active against microorganisms as claimed in claim 16 wherein said compound is tri-nhexyl bismuth.

23. The method for protecting a medium from attack by fungi which comprises applying to the locus to be protected, an effective amount of a compound R Bi wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl.

Coates, Organo-Metallic Compounds, John Wiley & Sons, Inc., New York, 1956, pp. 227-232.

Gilman et al Chem. Rev.," vol. 30, 1942, pp. 282, 287, 291, 295, 296, 314, and 315.

JULIAN S. LEVITT, Primary Examiner. 

23. THE METHOD FOR PROTECTING A MEDIUM FROM ATTACK BY FUNGI WHICH COMPRISES APPLYING TO THE LOCUS TO BE PROTECTED, AN EFFECTIVE AMOUNT OF A COMPOUND R3BI WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF ALKYL, ALKENYL, ALKYNYL, CYCLOALKYL, AND CYCLOALKENYL. 